The regulation of sterol and dolichol synthesis will be investigated in normal and malignant cells. These studies will be concerned, specifically, with structural features of the steroid molecule that are required for feedback inhibitory activity at the level of 3-hydroxy-3-methylglutaryl coenzyme A reductase; with the binding of inhibitory and non-inhibitory sterols to cytoplasmic receptors: with defining changes in the regulatory system that occur in transformed cell cultures; with determining which inhibitory sterols are produced in fibroblasts, tumors, and other non-hepatic cells; and with the regulation of dolichol synthesis and, consequently, of glycoprotein synthesis. The functions of cholesterol and dolichol in the production of cell membranes will be investigated by comparing the sterol, phospholipid, and carbohydrate composition and the microviscosity of plasma membranes from transformed and untransformed cell cultures, from tumor- and normal-cells in vivo and from cultured cells that have been depleted of sterol and in which other sterols have been substituted for cholesterol. The possibility that cell culture lines established in serum-containing media are specifically adapted to derive cholesterol from the media rather than by synthesis will be investigated. Lines of cells adapted to growth in media with and without serum will be compared. Various serum samples will be analyzed for the presence of inhibitory sterols. The effects of inhibitors of sterol synthesis such as 25-hydroxycholesterol and 7-ketocholesterol upon intact and tumor-bearing mice will be investigated.